Field of the Invention
Several embodiments of the present application relate generally to methods and compositions for the generation of pacemaker cells (e.g., cardiac cells that have regular, rhythmic electrical activity). In particular, some embodiments of the invention relate to gene and cell therapy methods (and associated compositions) to generate pacemaker cells using transcription factors.
Description of the Related Art
During cardiogenesis, cardiomyocytes become specialized to exhibit either ventricular, atrial, or pacemaker properties. The sinoatrial node (SAN), the primary pacemaker region of the heart, is a highly-specialized structure containing fewer than 10,000 pacemaker cells, which function to initiate contractions in the SAN. These SAN contractions then propagate to the rest of the excitable heart tissue and result in a heartbeat. Irregularities of excitable cardiac tissue and/or irregularities of pacemaker cells can lead to abnormalities in heart rhythm. Many cardiac abnormalities typically involve irregular heartbeat, tachycardia (where the heart rate is too high), or bradycardia (where the heart rate is too slow). These abnormalities are collectively known as arrhythmias.
Current therapies for cardiac arrhythmias typically rely on drug therapy, ablation, electronic pacemaker devices or combinations thereof. However, the usefulness of each of these therapies has met with limited and varying success. While antiarrhythmic drugs are widely prescribed and used, they may result in adverse systemic side effects in certain patient populations. Further, many drugs have a propensity to provoke new arrhythmic events, which can lead to an increase in morbidity. Radiofrequency ablation is used in some treatments of arrhythmias. Ablation involves permanent removal of the tissue identified as the source of, or critical to, the maintenance of the arrhythmias. While this method has found some success in the treatment of atrioventricular node reentry tachycardia, accessory pathway tachycardia, and atrial flutter, it has found limited success in the treatment of other arrhythmias. For instance, catheter ablation is less successful in treating more complex cases, such as atrial fibrillation (AF) or ventricular tachycardia (VT). Moreover, catheter ablation is not useful in the treatment of bradycardia. Electronic pacemaker devices can sustain heart rate, or deliver shocks to terminate tachycardias. However, the high cost of devices, and complications such as pulmonary collapse, hemorrhage, bacterial infection, and lead/generator failure or other types of malfunction represent limitations of the technology.